Biological Membranes - A. N. Ogurtsov 2012

Electrogenesis of Biomembranes
Intracellular Signaling
Signaling Function of Biomembranes

Cell/30.html">The Plasma Membrane of a cell contains molecular complexes that convert extracellular signals into intracellular ones. Receptors recognize signaling molecules and trigger intracellular signal Transduction pathways, which ultimately lead to the Regulation of cellular processes such as secretion, contraction, METABOLISM, or growth.

Intracellular signals are spread within The Cell by messenger molecules—secondary messengers (or simply messengers).

At THE MOLECULAR LEVEL, The process of Transmembrane Signal Transduction is mediated by a chain of Membrane Proteins that interact with one another sequentially.

Each successive interaction induces a conformational shift in the next protein down the chain, altering its Structure and, consequently, its function.

Molecular machines responsible for transmitting signals from receptors to intracellular targets typically consist of several protein components, collectively referred to as a signaling cascade or simply a cascade.

The protein components of signaling cascades are called protein messengers or mediators.

At a certain stage of the cascade, the further transmission of information is delegated to small molecules or even ions located in the Cytoplasm. These serve as secondary messengers, and their rapid diffusion ensures the prompt Propagation of the signal throughout the entire cell.

It is customary to use the term messenger rather than mediator for signaling molecules. The reason is that both various proteins and small molecules (the actual secondary signals) are involved in signal transduction within the cytoplasm, and functionally all of them act as mediators between the receptor—stimulated by an external stimulus—and the cellular response.

However, There is a fundamental difference between them: proteins form a distinct molecular machine that, on the one hand, Senses the external signal and, on the other, possesses enzymatic or other activity modulated by that signal, whereas small molecules truly act as messengers (couriers or dispatchers) between various proteins, multienzyme complexes, or even cellular structures.

The most commonly used messengers are:

✵ cyclic adenosine monophosphate (cAMP);

✵ cyclic guanosine monophosphate (cGMP);

✵ Inositol trisphosphate (IP₃);

✵ diacylglycerol (DAG);

✵ calcium cation (Ca²⁺).

The number of distinct secondary messengers is surprisingly small. In other words, intracellular signal transduction pathways are universal and capable of regulating A wide variety of PHYSIOLOGICAL AND BIOCHEMICAL processes.

Two main signal transduction pathways are distinguished.

In one of them, cyclic adenosine monophosphate (cAMP) serves as The secondary messenger.

In the other, a combination of three secondary messengers operates: Calcium Ions, inositol trisphosphate, and diacylglycerol. The latter two substances are generated directly within the plasma membrane.

These two signaling pathways share much in common. Figure 138 illustrates a GENERALIZED SCHEME OF membrane receptor signaling, the MAIN STAGES OF which are present in membrane signaling mechanisms across various cell types.

In both cases, the elements that receive information from the initial component—the receptor—and transmit it across the membrane into the cell interior are so-called G proteins, which are membrane GTPase proteins activated upon binding guanosine triphosphate.

G proteins activate an intracellular amplifying enzyme, which in turn converts precursor molecules into secondary messenger molecules.

The operation of this membrane conveyor can be broken down into four consecutive stages.

Stage One (Figure 138(a,b)). A signaling molecule, such as a hormone (1) (Figure 138(a)), is delivered via the bloodstream or Lymphatic system to a GPCR (G-protein coupled receptor) (2).

The binding of the hormone to the receptor induces a structural transformation that alters the conformation of the intracellular domain of the receptor protein, converting it into a nucleotide exchange factor for the G protein (3) (Figure 138(b)) (GEF protein — Guanine nucleotide Exchange Factor (Figure 79)).

The Second Stage (Figure 138(c,d,e)). The G protein diffuses laterally along the membrane and binds to the hormone-activated GPCR membrane receptor (Figure 138(b)). This event stimulates the replacement of the GDP molecule attached to the G protein with a GTP molecule (Figure 138(d)), which in turn causes a sharp decrease in the affinity of the hormone-activated membrane receptor (2) for the G protein-GTP complex (3) and the hormone (1) (Figure 138(e)). The GTP-bound G protein and the hormone (1) dissociate from the receptor (Figure 138(e)).

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Figure 138 - Step-by-step diagram of membrane reception: 1 - hormone (signaling molecule); 2 - GPCR receptor protein; 3 - G protein; 4 - membrane enzyme; 5 - substrate; 6 - extracellular space; 7 - cell Cytosol

The Third Stage (Figure 138(e,f)). The G protein diffuses along the membrane and binds to the inactive enzyme (4) (Figure 138(e)). The terminal phosphoryl group of GTP is transferred to the enzyme. Enzyme phosphorylation induces a conformational change, forming the required Spatial Structure of the Active Site, thereby making the enzyme catalytically active (Figure 138(f)).

The Fourth Stage (Figure 138(g,h,i)). The activated enzyme (4) binds the substrate (5) (Figure 138(g)) and catalyzes its conversion (Figure 138(h)). The transformed substrate leaves the enzyme (Figure 138(i)) and triggers intracellular processes, which constitute the cellular response to the external signal.

If the transformed substrate activates Other Enzymes, it Functions as a secondary messenger.

The most Characteristic Properties of a secondary messenger are:

1. Secondary messengers have a relatively low molecular weight compared to Biopolymers, since a messenger molecule must diffuse rapidly through the cytoplasm.

2. A secondary messenger must be degraded rapidly (relative to the signal transmission time), or, in the case of Ca²⁺, pumped out of the cytosol. Otherwise, the signaling system would remain activated even after the external signal has ceased.

Such malfunctions can be literally fatal. For instance, phorbol esters, which are structural analogs of diacylglycerol (Figure 15(6)) but are not degraded in the body, promote malignant tumor development. This occurs because phorbol esters become involved in certain signaling systems that regulate Cell Division via diacylglycerol acting as a secondary messenger. However, by mimicking the action of DAG and transmitting a proliferative signal, they fail to undergo timely degradation. As a result, the signaling system loses responsiveness to external cues and remains permanently locked in the 'on' state, meaning that cell proliferation (division) escapes regulation.

Below we will examine some Examples of membrane signal transduction systems.